Obesity means a condition wherein energy intake continuously exceeds energy consumption and thus neutral lipids accumulate in adipocytes, which results in a remarkable increase in body weight compared with normal body weight (Eiji ITAGAKI, STEP Taisha-Naibunpitsu (STEP Metabolism and Endocrine Secretion), Kaiba Shobo, 1st ed., 1998, p. 105: Non-patent Document 1). It is known that the excessively accumulated lipids induce, for example, insulin resistance, diabetes, hypertension, hyperlipidemia and so on and a combination of a plural number of these factors highly increases the risk of the onset of atherosclerosis. These symptoms are called metabolic syndrome. Furthermore, it is known that hypertriglyceridemia or obesity increases the risk of the onset of, for example, pancreatitis, impaired liver function, cancer such as mammary cancer, uterine cancer, ovary cancer, colon cancer or prostatic cancer, menstrual disorder, arthritis, gout, cholecystitis, gastro-esophageal reflux, obesity-hypoventilation syndrome (Pickwickian syndrome), sleep apnea and so on. It is widely known that diabetes often leads to, onset of, for example, angina pectoris, heart failure, stroke, claudication, retinopathy, failing vision, renal failure, neuropathy, skin ulcer, infection and so on [The Merck Manual of Medical Information, second home ed., Merck & Co., 2003: Non-patent Document 2].
LCE occurring in endoplasmic reticula in cells is an enzyme which belongs to the group of enzymes catalyzing carbon chain elongation reactions of fatty acids having carbon chains consisting of 12 or more carbon atoms and catalyzes the rate-controlling condensation step. In mammals, many fatty acids newly synthesized in vivo have carbon chains consisting of 16 to 18 carbon atoms. These long chain fatty acids amount to more than 90% of the total fatty acids occurring in cells. These fatty acids are important constituents of membranes. Also, they are important components of fat tissues which are the largest energy storage organs in animals. New fatty acid synthesis occurs in the liver at the highest frequency. By this synthesis, excessive glucose in vivo is converted into fatty acids. Due to glycolysis, glucose is converted into pyruvate which is then converted into citrate in mitochondria and transported into the cytosol. ATP citrate lyase in the cytosol forms acetyl-CoA which is a precursor of a fatty acid and cholesterol. Acetyl-CoA is carboxylated by acetyl-CoA carboxylase (ACC) to give malonyl-CoA. Multifunctional fatty acid synthase (FAS) elongates a fatty acid by two carbon atoms using malonyl-CoA, acetyl-CoA and NADPH. The major final product of FAS in rodents is palmitoyl-CoA having a C16 carbon chain. This carbon chain of palmitoyl-CoA is further elongated by two carbon atoms by LCE [J. Biol. Chem., 276(48), 45358 to 45366, (2001): Non-patent Document 3]. It is known that excessive promotion of fatty acid synthesis in vivo induces an increase in neutral lipids and the like and, in its turn, results in lipid accumulation. For example, WO 2005/005665 (Patent Document 1) indicates a direct relationship between LCE and obesity. It is also reported that the expression amount of mouse FACE (LCE) varies depending on food intake [Matsuzaka T. et al., J. Lipid Res., 43(6):911 to 920 (2002): Non-patent Document 4].
It is known that LCE also occurs in protozoa and nematode and participates in the cell growth. In protozoa of the genus Trypanosoma causative of African trypanosomiasis (commonly called African sleeping sickness), for example, a long chain fatty acid is synthesized by a fatty acid-elongation pathway containing LCE. It is reported that the inhibition of the intracellular fatty acid elongation reaction affects the growth of the protozoa of the genus Trypanosoma [Lee S. H. et al., Cell, 126:691 to 699 (2006): Non-patent Document 5].
Therefore, it is expected that an LCE inhibitor is useful as a preventive and/or remedy for these diseases.
Although a part of the compounds according to the invention have been known in structure per se and these compounds have been commercially available, it has been neither disclosed nor suggested hitherto that these compounds have an LCE inhibitory effect.
Patent Document 1: WO 2005/005665
Non-patent Document 1: STEP Taisha-Naibunpitsu (STEP Metabolism and Endocrine Secretion, Kaiba Shobo, 1st ed., 1998, p. 105
Non-patent Document 2: The Merck Manual of Medical Information, second home ed., Merck & Co., 2003
Non-patent Document 3: J. Biol. Chem., 276(48), 45358 to 45366, (2001)
Non-patent Document 4: J. Lipid Res., 43(6):911 to 920 (2002)
Non-patent Document 5: Cell, 126:691 to 699 (2006)